B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR

A61M2202/00—Special media to be introduced, removed or treated

A61M2202/04—Liquids

A61M2202/0413—Blood

A61M2202/0415—Plasma

Abstract

Translated from Chinese

本发明涉及血浆净化膜和治疗疾病的血浆净化系统。 The present invention relates to the plasma membrane purification and treatment of diseases of plasma purification system.本发明的血浆净化膜是中空纤维血浆净化膜，该膜由疏水和亲水聚合物制造并具有海绵结构，在该结构中孔径从膜的外表面向内表面连续减小，其特征在于膜的断裂强度为50kgf/cm<sup>2</sup>或以上，在对牛血浆进行膜内侧向外过滤的情况下，总的蛋白透过率为50％或以上，免疫球蛋白(IgM)透过率为90％或以下。 Plasma purification membrane according to the present invention is a hollow fiber plasma purification membrane, the membrane made of a hydrophobic and a hydrophilic polymer and having a sponge structure, the pore size successively decreases from the inner surface of the outer surface of the film structure, characterized in that the breakage of the film strength was 50kgf / cm <sup> 2 </ sup> or more, in the case of bovine plasma side of the membrane filtration carried out, the total protein permeability of 50% or more, an immunoglobulin (IgM) through 90% or less.

Description

本发明涉及使用膜内侧向外过滤净化血浆的血浆净化膜和制造该膜的方法，所述膜很少堵塞且具有高强度。 The present invention relates to the use for the purified plasma inside the plasma membrane filtration purification membranes and methods of making the film, the film has high strength and rarely clog.本发明也涉及血浆净化系统和使用所述血浆净化膜治疗疾病的方法。 The present invention also relates to the use of plasma purification system and a method for purifying plasma membrane of treating a disease.

背景技术 Background technique

中空纤维膜已经广泛用于工业用途，例如微滤和超滤。 The hollow fiber membrane has been widely used for industrial purposes, such as microfiltration and ultrafiltration.关于膜使用的材料，已经使用了聚乙烯，纤维素乙酸酯，聚砜，聚偏二氟乙烯， 聚碳酸酯，聚丙烯腈或类似物。 About material film used, have been used polyethylene, cellulose acetate, polysulfone, polyvinylidene fluoride, polycarbonate, polyacrylonitrile, or the like.对这些材料形成的传统中空纤维膜进行研发的主要目标是提高过滤性能。 Traditional hollow fiber membrane formed of these materials were developed main goal is to improve the filtration performance.因此，由于传统中空纤维膜表现出低的断裂强度和断裂时的伸长，中空纤维膜由于快速温度变化或转换为逆洗时的压力变化而断裂。 Thus, since the conventional hollow fiber membranes exhibit changes in pressure due to rapid temperature change or convert the backwashing low elongation, the hollow fiber membrane at breaking and breaking strength and breaking.

为了解决该问题已经进行了各种尝试。 To solve this problem, various attempts have been made.如日本专利申请特开昭 As described in Japanese Patent Application Laid-Open No. Sho

59-228016 〃>开的发明所建议的，通常可以考虑这样一种方法，该方法通过增加制膜溶液中的聚合物浓度，使总的中空纤维膜的聚合物密度增加。 59-228016 〃> suggested disclosed invention generally may be considered a method of film formation by increasing the polymer concentration in the solution, the overall density of the polymer hollow fiber membrane is increased.该方法提高了膜的强度，但是减小了膜的孔径，并且大幅地减小了膜的通透性能。 This method improves the strength of the membrane, but the membrane pore size is reduced, and significantly reduces the permeability of the membrane.总之，还没有获得强度和通透性能良好平衡的中空纤维膜。 In summary, not yet been obtained a good balance of strength and permeability of the hollow fiber membrane.

为了提高膜的通透性能通常增加膜的孔径。 In order to improve membrane permeability can be generally increased membrane pore size.然而，孔径的增加通常减小膜的分级（截断）性能和强度。 However, increasing the grade of the film generally decreases pore size (cut) and strength.

如上所述，传统技术还没有获得强度、通透性能和分级性能具有良好平衡的高性能中空纤维膜。 As described above, the conventional techniques have not yet obtained the strength, permeability, and classification performance can be well-balanced, high-performance hollow fiber membranes.例如，日本专利申请特开平04-260424 提出了一种膜的制造方法，该膜具有高强度和优良的通透性能。 For example, Japanese Laid-Open Patent Application 04-260424 proposes a method for producing a film, the film has high strength and excellent permeability can.然而， 由于该方法获得的膜具有大孔径，因此通透性能和分级性能未被很好地平衡。 However, since the film obtained by this method has a large aperture, and therefore permeability of classification performance is not well balanced.

曰本专利申请特开平02-102722公开了一种中空纤维微滤膜，其中该膜的孔径从外表面向膜的内部连续减小，在膜的内部最小化，然后再次朝膜的内表面连续增加，并在内表面上开孔。 Said Patent Application Laid-Open 02-102722 discloses a hollow fiber microfiltration membrane, wherein the pore size of the membrane facing the interior of the film decreases continuously from the outer surface, inside the membrane is minimized, then continuously increases again toward the inner surface of the film and the inner surface of the opening.然而，当从具有该结构的膜的中空部（内表面侧）过滤液体或类似物时，由于发生快速堵塞而不能执行长时间稳定的过滤。 However, when the filter liquid or the like from the hollow portion (inner surface side) of the membrane having a structure, since the occurrence of clogging can not perform rapid and stable filtration for a long time.

日本专利特开昭58-155865公开了一种在中空纤维膜的至少一侧表面上具有致密层和在中空纤维膜内侧具有有孔层的中空纤维膜。 Japanese Patent Laid-open No. Sho 58-155865 discloses a dense layer on at least one surface of the hollow fiber membranes and hollow fiber membranes having a porous layer in the inside of the hollow fiber membranes.曰本专利申请特开昭58-155865公开了一种由乙烯醇聚合物制造的中空纤维膜，但是没有公开包含疏水聚合物和亲水聚合物的膜材料。 Said Patent Application Laid-Open No. Sho present 58-155865 discloses a hollow fiber membrane made from the vinyl alcohol polymer, but does not disclose a membrane material comprising a hydrophobic polymer and a hydrophilic polymer.如果亲水聚合物包含在疏水聚合物中，疏水聚合物彼此间的分子链变弱， 从而不能获得高强度。 If the hydrophilic polymer comprises a hydrophobic polymer, hydrophobic polymer between the molecular chains to each other is weakened, whereby a high strength can not be obtained.而且，由于日本专利申请特开昭58-155865中公开的由乙烯醇聚合物制造的中空纤维膜具有这样的结构，在该结构中致密层形成于膜的外表面上，因此当从膜的中空部（内表面侧）过滤液体或类似物时，由于发生堵塞而不能长时间稳定地进行过滤。 Further, since the Japanese Patent Application hollow fiber membranes made from the vinyl alcohol polymer-Open No. Sho 58-155865 Laid disclosed having such a structure, the structure is formed on the outer surface of the dense layer of film, so that when the hollow fiber membrane when the portion (inner surface side) of the filtered liquid or the like, due to the clogging can not be stably performed for a long time filter.

本发明的申请人已经提供了一种中空纤维膜，该膜包含疏水聚合物和亲水聚合物并具有海绵结构，其中孔径从膜的外表面向内表面连续减小。 The applicant of the present invention has been provided a hollow fiber membrane, the membrane comprising a hydrophobic polymer and a hydrophilic polymer and having a sponge structure, wherein the surface pore size successively decreases from the outer surface of the film.然而，该膜仅仅能够用于血液透析或超滤，其基本上不导致清蛋白从其中通过，不适合血浆净化（日本专利申请特开平1 1-309355,日本专利3281 364和日本专利3281 363 )。 However, the film can only be used in hemodialysis or ultrafiltration, which substantially does not lead to an albumin therethrough, are not suitable for the purification of plasma (Japanese Patent Application Laid-Open 11-309355, Japanese Patent No. 3281364 and Japanese Patent No. 3281363) .

如上所述，还未提供一种用于血浆净化的中空纤维膜，该膜被良好地平衡，并且表现出所希望的强度、通透性能和分级性能，甚至从中空部（内表面侧）的一侧过滤液体时很少堵塞。 As described above, has not provided a hollow fiber membrane for purifying blood plasma, the film was a good balance, and exhibits a desired strength, and permeability of classification performance, even from a hollow portion (inner surface side) of the rarely clogged filtration liquid side.

附图说明 BRIEF DESCRIPTION

图1是垂直于本发明的中空纤维膜的纵向方向的横截面的电子显樣i照片（》丈大率：xl， 500 )。 Figure 1 is an electron photograph of a cross-section like i perpendicular to the longitudinal direction of the hollow fiber membrane of the present invention ( "husband magnification: xl, 500).

图2是本发明的膜的内表面的电子显微照片（放大率：x 10, 000 )。 FIG 2 is an electron micrograph of the inner surface of the film of the present invention (magnification: x 10, 000).图3是本发明的膜的外表面的电子显微照片（放大率：x10，000 )。 FIG 3 is an electron micrograph of the outer surface of the film of the present invention (magnification: x10,000).图4是本发明的血浆净化系统的一个实施例的正视图。 FIG 4 is a front view of an embodiment of the plasma purification system according to the present invention.发明内容 SUMMARY

本发明的目标是提供一种血浆净化膜，该膜很少堵塞，具有高强度，并在使用膜内侧向外过滤的血浆净化中表现出优良的通透性能和分级性能。 Object of the present invention is to provide a plasma purifying film that rarely clogged, has high strength and exhibits excellent fractionation performance and permeability of the inner membrane filtration using plasma outwardly purification.本发明的另一个目标是提供一种血浆净化系统和使用该血浆净化膜治疗疾病的方法。 Another object of the present invention is to provide a plasma purifying system and method of the plasma membrane purification treatment of disease.

如上所述，还未提供一种血浆净化膜，该膜很少堵塞，并且当从膜的中空部过滤液体或类似物时（下面可以称为"膜内侧向外过滤，，） 表现出优良的蛋白分离特性。这是因为不可能形成带有大孔径（在微滤膜范围的孔径）的孔，同时又保持膜的强度，所述大孔径允许血浆蛋白从其中通过并进入具有梯度结构的膜的内表面，在该梯度结构中孔径从膜的外表面向内表面连续减小。 As described above, has not provided a plasma purification membrane, the membrane clogging rarely, and when the filtered liquid or the like from the hollow portion of the film (hereinafter may be called "inner filter membrane outwardly ,,) exhibit excellent protein separation characteristics. this is because it is impossible with a large diameter hole formed (microfiltration membrane pore size range), while maintaining the strength of the film, a large aperture to allow plasma proteins to pass therethrough and into the membrane having a gradient structure an inner surface, the gradient in the pore structure decreases continuously from the inner surface of the outer surface of the film.

为了防止堵塞而形成梯度结构，在该梯度结构中孔径从膜的外表面向内表面连续减小，和2)增加膜的内表面的亲水性，其被过滤的液体接触，从而蛋白或类似物不会受到疏水性吸附。 To prevent clogging of a gradient structure is formed, the surface pore size continuously decreases in a gradient from the outer surface configuration of the film, and 2) increase the hydrophilicity of the inner surface of the film which contacts the liquid to be filtered, so as protein or the like It will not be hydrophobic adsorption.总之，本发明已经发现了所需的膜，该膜能够通过使用特殊的制造方法而获得。 In summary, the present inventors have found that the desired film, the film can be obtained by using a special manufacturing method.该发现导致了本发明的实现。 This finding has led to the realization of the present invention.

从下面详细的说明书和附加的权利要求中，本发明的上述和其它目标、特征和优点将变得明显。 From the following detailed description and appended claims, the above and other objects, features and advantages of the present invention will become apparent.

根据本发明，能够提供了一种血浆净化膜，该膜很少堵塞，具有高强度，并且在使用膜内侧向外过滤的血浆净化中表现出优良的通透特性和分级性能。 According to the present invention, there is provided a plasma purification membrane, the membrane clogging rarely, has high strength and exhibits excellent fractionation performance and permeability properties using the plasma side of the membrane filtration purification outwardly.

为了便于更好地理解本发明，在下面给出了本发明的基本特征和优选实施例。 To facilitate a better understanding of the invention, are given below and the basic characteristics of the present preferred embodiment of the invention.

(1) 一种中空纤维血浆净化膜，包含疏水聚合物和亲水聚合物并具有海绵结构，在该结构中孔径从膜的外表面向内表面连续减小，具 (1) A hollow fiber plasma purification membrane, comprising a hydrophobic polymer and a hydrophilic polymer and having a sponge structure, the pore size successively decreases from the inner surface of the outer surface of the film structure, having

有50kgf/cr^或以上的断裂强度，当对牛血浆进行膜内侧向外过滤时， 总的蛋白透过率为50%或以上，免疫球蛋白（IgM)透过率为90%或以下。 There 50kgf / cr ^ breaking strength or more, when the inner membrane of the bovine plasma was filtered out, the total protein permeability of 50% or more, an immunoglobulin (IgM) permeability of 90% or less.

(2) 根据上述（1)的中空纤维血浆净化膜，所述膜具有圓形或椭圆形孔，所述孔在膜的外表面上具有1 pm或以上的平均孔径。 (2) Purification of the above (1) a hollow fiber plasma membrane, the membrane has a circular or oval apertures having an average pore diameter of 1 or more PM on the outer surface of the membrane.(3) 根据（1)或（2)的中空纤维血浆净化膜，其中膜的外表面的孔隙率为10%或以上。 (3) purification membrane according to (1) or (2) a hollow fiber plasma, wherein the porosity of the outer surface of the film is 10% or more.

(5) 根据（1)至（4)之一的中空纤维血浆净化膜，其中所述膜具有400lam或以下的外径。 (5) According to (1) to (4), one hollow fiber plasma purification membrane, wherein said membrane has an outer diameter 400lam or less.

(6) 根据（1)至（5)之一的中空纤维血浆净化膜，其中所述膜包含芳族聚砜和聚乙烯吡咯烷酮，并且聚乙烯吡咯烷酮在膜的内表面上的浓度为20 - 45wt% 。 (6) according to (1) to (5), one hollow fiber plasma purification membrane, wherein the membrane comprises an aromatic polysulfone and polyvinylpyrrolidone, and a polyvinylpyrrolidone concentration on the inner surface of the film is 20 - 45wt %.

用于治疗与年龄有关的黄斑变性患者。 For the treatment of patients with age-related degeneration of the macula.

(10) 根据（1)至（8)之一的中空纤维血浆净化膜，其中所述膜用于治疗高脂血症患者。 (10) According to (1) to (8), one hollow fiber plasma purification membrane, wherein the membrane for treating patients with hyperlipidemia.

(11) 一种制造中空纤维血浆净化膜的方法，该膜包括疏水聚合物和亲水聚合物并具有海绵结构，在该结构中孔径从膜的外表面向内表面连续减小，具有50kgf7ci^或以上的断裂强度，当对牛血浆进行膜内侧向外过滤时，总的蛋白透过率为50%或以上，免疫球蛋白（IgM) 透过率为90%或以下，该方法包括以下步骤：从双环形喷嘴排出制膜溶液和内部溶液，使排出的混合物通过气隙，在凝固浴中凝固产生的混合物； (11) A method of manufacturing a hollow fiber plasma purification membrane, the membrane comprising a hydrophobic polymer and a hydrophilic polymer and having a sponge structure, the surface pore size continuously decreases from the outer surface configuration of the film, or having 50kgf7ci ^ above the breaking strength, when the inner membrane of the bovine plasma was filtered out, the total protein permeability of 50% or more, an immunoglobulin (IgM) permeability of 90% or less, the method comprising the steps of: discharging from the double annular nozzle membrane-forming solution and an internal solution, the mixture is discharged through the air gap, the resulting mixture was coagulated in a coagulation bath;

该方法进一步的特征在于： The method further characterized by:

a)制膜溶液包含疏水聚合物，疏水聚合物的溶剂，和亲水聚合物， 亲水聚合物对疏水聚合物的比率为27 - 60wt%; a) a solution comprising a hydrophobic film-forming polymer, a solvent for the hydrophobic polymer and hydrophilic polymer, the ratio of hydrophilic polymer to hydrophobic polymer is 27 - 60wt%;

b )内部溶液包含水和至少一种溶剂，并具有40 - 55wt %的水含量； c)喷嘴处的制膜溶液具有5(TC或以上的温度； b) the internal solution comprises water and at least one solvent, and of 40 - Water content 55wt%; c) a membrane-forming solution having a nozzle (TC temperature for 5 or more;

(12) 根据（11)的制造中空纤维血浆净化膜的方法，进一步包括对膜应用辐射的步骤。 (12) The method (11) for producing a hollow fiber plasma purification membrane, the membrane further comprising the step of the application of radiation.

(13) 根据（11)或（l2)的制造中空纤维血浆净化膜的方法， 其中疏水聚合物是聚砜聚合物。 (13) The method of (11) or (L2) of producing a hollow fiber plasma purification membrane, wherein the hydrophobic polymer is a polysulfone polymer.

(14) 根据（11)至（13)中任一制造中空纤维血浆净化膜的方法，其中疏水聚合物的溶剂是N-曱基-2-吡咯烷酮。 (14) (11) to (13) of any one of a hollow fiber plasma purification membrane The method of manufacturing a solvent in which the hydrophobic polymer is N- Yue-2-pyrrolidinone.

(15) 根据（11)至（14)中任一制造中空纤维血浆净化膜的方法，其中纺速为60m/min或以上。 (15) (11) to (14) of any one of a method for producing a hollow fiber plasma purification membrane, wherein the spinning speed was 60m / min or more.

(16) —种血浆净化系统，其包括：血浆分离器，其包括将血液分离成血细胞成分和血浆成分的分离膜；血浆成分分离器，其包括将经分离的血浆成分分离成致病物质和致病物质已除去或减少的血浆成分的分离膜；第一混合装置，其用于混合致病物质已除去或减少的血浆成分和补给溶液；第二混合装置，其用于进一步混合经过第一混合装置的血浆成分和血浆分离器分离的血细胞成分；其中包括在血浆成分分离器中的分离膜是根据（l)至UO)中任一所述的膜。 (16) - species plasma purification system, comprising: a plasma separator, comprising separating blood into a blood cell component and a plasma component separation; plasma component separator, which comprises separating the plasma component is separated into pathogenic substances and the plasma component separation causative agent has been removed or reduced; a first mixing means for mixing the causative agent has been removed or reduced plasma component and replenishing solution; second mixing means for further mixing through the first a plasma component separator and plasma mixing device isolated blood cell component; wherein the separation membrane comprises a plasma component separator is a membrane (l) to UO) in accordance with any one of.

(17) 根据（16)的血浆净化系统，进一步包括加热混合血浆成分和血细胞成分的第二混合装置上游的血浆的装置。 (17) (16) of the plasma purification system, further comprising a second mixing means of plasma heating means upstream of the mixing of blood plasma component and the cell components.

却血浆分离器下游和血浆成分分离器上游的血浆的装置。 Cooling means downstream of the plasma and the plasma separator upstream of the plasma component separator.

(19) 根据（16)至（18)中任一血浆净化系统，其中包括从血 (19) a plasma purification system according to any of (16) to (18), which includes from the blood

浆成分分离器排出的致病物质的排出液量等于补给溶液的量。 A liquid discharge amount of the pathogenic substances discharged from the plasma component separator is equal to the amount of replenishment solution.

(20) 根据（16)至（l9)中任一血浆净化系统，其这样控制， 使得从血浆分离器到血浆成分分离器的血浆供给量等于返回到第二混 (20) (16) to (L9) of any one of plasma purification system so controlled, that the return from the plasma separator is equal to the amount of plasma supplied to the plasma component separator second mixer

合装置的血浆量。 Engagement means plasma volume.

(21 )根据（16)至（20)中任一血浆净化系统，进一步包括检测在第二混合装置下游和血液出口的上游的气泡的装置。 (21) (16) to plasma purification system of any one of (20), further comprising detecting means in the bubble upstream of the second mixing means and downstream of a blood outlet.

(22) —种血浆净化方法，包括使用根据（"）至（21)中任一 (22) - species plasma purification method, comprising using the ( ") to (21) of any one of

9血浆净化系统。 9 plasma purification system.

(23) —种治疗疾病的方法，包括使用根据（16)至（21)中任一血浆净化系统处理活体的血液。 (23) - method of treating a disease, comprising the use of blood (21) of any one of the processing plasma purification system according to the living body (16) to.

(20 —种治疗与年龄有关的黄斑变性患者的方法，包括使用根据（16)至（n)中任一血浆净化系统。 (20 - the kind of treatment of patients with age-related degeneration of the macula, including the use of (16) to (n) a plasma purifying system according to any.

(25)—种治疗高脂血症患者的方法，包括使用根据（16)至（21 ) 中任一血浆净化系统。 (25) - methods for treating hyperlipidemia in a patient, comprising the use of a plasma purification system according to any of (16) to (21).

下面描述了本发明的中空纤维血液净化膜（以下可以简称为"膜，， 或"中空纤维膜"）的结构。 The following describes a hollow fiber blood purification membrane according to the present invention (hereinafter may be simply referred to as "film ,, or" hollow fiber membrane ") structure.

在本发明中，血浆净化表示分离血浆中的成分。 In the present invention, showing the plasma purifying plasma component separator.例如，血浆净化表示使血浆中诸如清蛋白和Y球蛋白的有用蛋白透过，并除去不必要的蛋白和脂质。 For example, indicates that the purified plasma as plasma albumin and globulins useful proteins through Y, and removing unwanted proteins and lipids.然而，由于去除的目标成分，分级分离（截断）分子量，和类似的差别取决于疾病类型，因此本发明中的血浆净化广泛地包括血浆中的成分分离。 However, since the target component removed, fractionation (cut) the molecular weight, and the like differs depending on the type of disease, plasma and therefore purification of the present invention broadly comprises a separate plasma component.

本发明的中空纤维膜具有一种结构，在该结构中所述膜由从一个表面到另一表面一体化地和连续地形成，例如从膜的内表面到外表面。 The hollow fiber membrane of the present invention has a structure, in the structure of the film from one surface to the other and integrally continuously formed, for example, from the inner surface to the outer surface of the film.膜的一个表面到另一表面的膜内部具有网眼结构，网眼（孔）大小为lOiam或以下，不包括孔径超过10Mm的聚合物缺损部位（大孔或空穴）。 A surface of the film to the inside of the membrane having a mesh structure of the other surface, a mesh (pore) size lOiam or less, not including an aperture defect site than 10Mm polymer (macropores or voids).在本发明中，该结构表示海绵结构。 In the present invention, showing the structure of a sponge structure.

膜内部网眼结构的孔具有梯形结构，在该结构中孔径在垂直于膜纵向的横截面中从膜的外表面向内表面（或内表面区域）连续减小。 Mesh structure inside the membrane pores having a ladder structure, a pore size continuously decreases in the cross-section perpendicular to the longitudinal direction of the film toward the inner surface (or inner surface area) from the outer surface of the film structure.特别地，假设一些圆柱形表面与在中空纤维膜的纵向方向延伸的中心轴同心，在每个圓柱形表面的孔的平均孔径从膜的外表面向内表面（或内表面区域）连续减小。 In particular, assuming that some of the cylindrical surface concentric with the central axis extending in the longitudinal direction of the hollow fiber membrane, the average pore diameter of each hole from the outer cylindrical surface of the membrane toward the inner surface (or inner surface area) decreases continuously.当血浆进行膜内侧向外过滤时该结构对于保证快速分级性能（极佳的蛋白质分离性能）是不可缺少的。 When the plasma membrane-inner filter outwardly for the structure to ensure fast classification performance (excellent protein separation performance) it is indispensable.

下面参考附图详细描述了本发明的膜的典型实例。 Typical examples are described in detail below film of the present invention with reference to the accompanying drawings.

图1是垂直于中空纤维膜的纵向方向的横截面（部分）的电子显微照片。 FIG 1 is a cross section perpendicular to the longitudinal direction of the hollow fiber membranes (partial) electron micrograph.图2是显示膜的内表面状态的电子显微照片。 FIG 2 is a graph showing the surface state electron micrograph of the film.图3是显示膜的外表面状态的电子显微照片。 FIG 3 is a state of the film surface of the outer electron micrograph.如图1所示，该膜具有梯形结构，在该结构中平均孔径向膜的内表面逐渐地和连续地减小，即，具有孔径各向异性的网眼结构。 As shown in FIG. 1, the film having a ladder structure, the average pore size is gradually and continuously decreases toward the inner surface of the membrane in this configuration, i.e., having an anisotropic pore network structure.膜的内表面具有致密结构。 The inner surface of the film has a dense structure.然而，本发明的膜不具有本领域公知的明确皮 However, the film of the present invention does not have clearly known in the art of transdermal

层（skin layer)。 Layer (skin layer).图2显示了致密内表面的状态。 2 shows a state in which a dense surface.另一方面，在图3所述的外表面上也观察到了圆形或椭圆形孔。 On the other hand, was observed on the outer surface according to FIG. 3 circular or elliptical holes.

开口于膜的内表面上的孔优选为圆形、椭圆形、网眼状或缝隙状。 Preferably the hole openings on the inner surface of the film is circular, oval, slit, or a mesh-like shape.开口于膜的外表面上的孔优选为圆形或椭圆形。 Opening a hole in the film outer surface is preferably circular or elliptical.

开口于膜的外表面上的孔的平均孔径为ljiira或以上，优选为2pra 或以上，但是在30jiim以下。 The average pore diameter of the opening in the outer surface of the film is ljiira or more, preferably 2pra or more, but less 30jiim.如果孔径小于lym，由于膜之间的粘结可能导致成型失败。 If the diameter is smaller than lym, since the adhesion between the film may cause molding failure.

为了防止膜之间的粘结，外表面的孔隙率也是重要的。 In order to prevent adhesion between the film, the porosity of the outer surface is also important.可以通过图像分析干燥膜外表面的电子显微照片，将图像分析结果转化为数字值而确定本发明中使用的孔隙率。 By image analysis of the electron micrograph of the outer surface of the dried film, the image analysis result into a digital value determining the porosity used in the present invention.本发明中使用的孔隙率由多孔部中孔的总面积相对于照片图像的面积的百分比定义，并由下面的等式（1 ) 表示。 The total area of ​​pores in the porosity of the porous portion in the present invention is defined as a percentage relative to the area of ​​the photographic image, by the following equation (1).具有IO像素或以下尺寸的孔作为干扰从计算中排除。 IO pixel having the following dimensions or pore excluded from the calculation as an interference.

孑L隙率（％ )=(多孔部中孔的总面积/照片图像的面积）xiOO Larvae L porosity (%) = (the total area of ​​pores in the porous portion / photo image) xiOO

m m

孔隙率显著地影响膜的粘结。 Porosity significantly affect the adhesive film.如果孔隙率小，由于相邻膜之间接触面积增加而发生粘结。 If the porosity is small, since the contact area between adjacent film bonding occurs.在最坏的情况下，整个束粘结成棒状。 In the worst case, the whole beam bonded into a rod.因此， 孔隙率必须为10%或以上。 Thus, the porosity must be 10% or more.然而，如果孔隙率不必要地增加，在纵向方向膜的弹性降低，即弹性强度减小，因此，由于在粘结部分的膜流动和运动，在成型期间经常发生成型失败。 However, if the porosity increases unnecessarily, in the longitudinal direction of the film elasticity, i.e. elastic strength is reduced, and therefore, since the movement of the film and the bonding portion of the flow of molding failure often occurs during the molding.因此，为了不削弱弹性强度，孔隙率优选必须为60%或以下。 Therefore, in order not to impair the elastic strength, the porosity preferably must be 60% or less.

可以通过使用电子显微镜观察和测量开口于膜表面的孔的形状、 尺寸等。 The like can be observed using an electron microscope and measuring the film surface open to the hole shape, size.

开口于内表面或外表面的孔的平均孔径D由下面的等式（2 )表示。 Opening a hole in the inner or outer surface of the average pore diameter D is expressed by the following equation (2).D- [ ((Di2)2 + ....,.+ (Dn2")/(Di2 + D?)r" (2) 在等式（2)中，D表示平均孔径，Di表示第i个孔的测量直径， Dn表示第n个孔的测量直径。当孔基本为圓形时，Di或Dn的测量直径由孔的直径表示。当孔不是圆形时，Di或Dn的测量直径由与孔的面积相同的圆的直径表示。 D- [((Di2) 2 ​​+ ....,. + (Dn2 ") / (Di2 + D?) R" (2) In Equation 2) (, D represents an average pore diameter, Di denotes the i th measuring the diameter of the holes, Dn represents the n-th measurement of the diameter of the hole when the hole is substantially circular, the diameter measurement Di or Dn is represented by the diameter of the hole when the hole is not circular, the diameter Di measured by the or Dn the same area of ​​the hole diameter of a circle expressed.

当对牛血浆进行膜内侧向外过滤时，本发明的膜具有50%或以上的总蛋白的透过率，优选80%或以上。 When the inner membrane of bovine plasma was filtered out, the film of the invention having a transmittance of 50% or more of total protein, preferably 80% or more.如果总的蛋白透过率小于50 %,则相当多的清蛋白（Alb)和y球蛋白（IgG)(分子量大约为160，000 )损失，这些蛋白对身体是十分必要的，因此很难使用该膜治疗体力减弱的病人。 If the total protein permeability of less than 50%, a considerable amount of albumin (Alb) and y globulin (IgG) (molecular weight of approximately 160,000) loss of these proteins is necessary for the body, making it difficult to use the film treatment of patients physically weakened.

当对牛血浆进行膜内侧向外过滤时，本发明的膜具有90%或以下的免疫球蛋白UgM)(分子量大约为950， 000 )透过率。 When the inner membrane of bovine plasma was filtered out, the film of the present invention is 90% or less of immunoglobulins UGM) (molecular weight of about 950, 000) transmittance.因为清蛋白和Y球蛋白是身体非常需要的蛋白，取决于疾病的类型，必须除去诸如免疫球蛋白的高分子量的蛋白或脂质。 Y as albumin and globulin proteins are highly desirable body, depending on the type of the disease, must remove high molecular weight proteins such as immunoglobulins or lipids.如果透过率超过90%，该膜不能有效地治疗诸如高脂血症这样的疾病。 If the transmittance exceeds 90%, the film is not effective to treat such diseases as hyperlipidemia.

即使发明的膜具有梯度结构，在该结构中孔径从膜的外表面向内表面连续减小，并包括具有大孔径的孔，该大孔径允许血浆蛋白穿过膜的内表面，该膜仍具有50kgf/ci^或以上的断裂强度，优选60kgf/cin2 或以上。 Even if the invention has a gradient structure film, the surface of the pore size successively decreases from the outer surface configuration of the film, and includes an aperture having a large aperture, which aperture allows a large plasma protein across the inner surface of the film, the film still has 50kgf / or more of the breaking strength of ci ^, preferably 60kgf / cin2 or more.如果膜的断裂强度小于50kgf/cm2,会发生明显的渗漏或类似情况。 If the breaking strength of the film is less than 50kgf / cm2, apparent leakage or the like occurs.通过用施加给一个中空纤维膜的断裂负荷（kgf )除以施加负荷之前膜的横截面积（cm2)，可以确定本发明中使用的断裂强度。 Applied load divided by the cross sectional area of ​​the film before (cm2) through a breaking load of the hollow fiber membranes (kgf) applied to the use, the breaking strength may be determined for use in the present invention.

本发明的中空纤维膜包括疏水聚合物和亲水聚合物。 The hollow fiber membrane of the present invention comprises a hydrophobic polymer and a hydrophilic polymer.

作为疏水聚合物的实例，可以是聚砜聚合物，聚乙烯聚合物，聚丙烯聚合物，聚偏二氟乙烯聚合物等。 As examples of hydrophobic polymer may be polysulfone polymers, polyethylene polymers, polypropylene polymers, polyvinylidene fluoride polymers.从湿式制膜的观点来看，聚砜聚合物和聚偏二氟乙烯聚合物是优选的。 From the viewpoint of view wet film, polysulfone polymers and polyvinylidene fluoride polymers are preferred.其中，由于芳族聚砜具有热稳定性、耐酸和耐碱性，通过向制膜溶液中添加亲水聚合物和使用所产生的溶液制造膜，其能够提高血液相容性，因此最优选使用芳族聚砜。 Wherein the aromatic polysulfone has since thermal stability, acid and alkali resistance, by adding a solution of hydrophilic polymer and producing a film using the generated solution to the film, which can improve the blood compatibility is most preferred to use aromatic polysulfone.作为芳族聚砜，尤其优选使用双酚A聚砜。 As the aromatic polysulfone, particularly preferably bisphenol A polysulfone.

不特别地限定疏水聚合物，只要聚合物可以在水中膨胀但不溶于水。 Hydrophobic polymer is not particularly limited, as long as the polymer can swell in water but insoluble in water.这种聚合物的实例为包含取代基的聚合物，取代基为例如磺酸基， Examples of such polymers is a polymer containing substituents, substituents, for example, a sulfonic acid group,

12啶基，吡咯烷酮基，咪唑基，和季铵基，或者单独，或者两个或多个的组合。 12, piperidinyl, pyrrolidinonyl, imidazolyl, and quaternary ammonium groups, either alone, or in combination of two or more.

为了湿式制膜，可以作为亲水聚合物使用的是与溶剂可混但与疏水聚合物不可混的聚合物。 To wet film may be used as the hydrophilic polymer is miscible with the solvent but immiscible polymer hydrophobic polymer.当构成中空纤维膜的疏水聚合物是芳族聚砜时，聚乙烯吡咯烷酮是最优选的亲水聚合物。 When the hollow fiber membranes constituting the hydrophobic polymer is an aromatic polysulfone, polyvinyl pyrrolidone is most preferred hydrophilic polymer.

如上所述，本发明的膜最优选包含芳族聚砜和聚乙烯吡咯烷酮。 As described above, the film of the present invention most preferably comprises an aromatic polysulfone and polyvinylpyrrolidone.由于本发明的血浆净化膜用于膜内侧向外过滤，血浆与之接触的膜内 Since the plasma membrane of the present invention for purifying the inside of the membrane filter outwardly, in contact with the plasma membrane

到疏水性吸附。 The hydrophobic adsorption.因此，防止膜内侧向外过滤期间堵塞的重要因素是血浆与之接触的膜内表面的亲水性。 Thus, an important factor to prevent clogging of the membrane inside the filter during the outward hydrophilic surface plasma membrane in contact therewith.在包含聚乙晞吡咯烷酮（以下可以 Xi may comprise polyvinyl pyrrolidone (hereinafter

简称为"PVP")的聚砜膜中，膜内表面的PVP浓度是重要的。 Polysulfone membrane abbreviated as "PVP") in, PVP concentration of the membrane surface is important.如果膜内表面的PVP浓度太低，膜内表面表现出疏水性，从而血浆蛋白容易被吸附到膜内表面。 If the PVP concentration is too low the film surface, the film surface exhibits hydrophobicity, such plasma proteins are adsorbed onto the membrane surface is easy.如果膜内表面的PVP浓度太高，溶出进入血浆中的PVP量增加，可能导致不希望的结果。 If the PVP concentration is too high the film surface, the amount of PVP eluted into the plasma is increased, it may lead to undesirable results.因此，当进行膜内侧向外过滤期间PVP浓度为20 - 45wt%,优选25 - 40wt%。 Therefore, while the inner membrane filtration carried out when the concentration of PVP is 20 - 45wt%, preferably 25 - 40wt%.

作为用于本发明的聚砜聚合物，可以是包括由下面分子式（3)或(4)表示的重复单位的聚合物。 Polysulfone polymer as used in the present invention may be a polymer comprising repeating units represented by the following formula (3) or (4).在该分子式中，Ar表示二代（对位） In this formula, Ar represents the second generation (para)

苯基，聚合程度和分子量未作特别限定。 A phenyl group, molecular weight and degree of polymerization is not particularly limited.

-0 - Ar - S02 - Ar - （4) 由于具有越高分子量的聚乙烯吡咯烷酮在膜上施加越高的亲水作用，用较少量的添加物就能获得足够的效果。 -0 - Ar - S02 - Ar - (4) because of the hydrophilic effect of the higher molecular weight polyvinyl pyrrolidone applied higher on the film, with a smaller amount of additives sufficient effect can be obtained.因此，本发明使用重均分子量为900， GOO或以上的聚乙烯吡咯烷酮。 Accordingly, the present invention is used as a weight-average molecular weight of 900, GOO or more polyvinylpyrrolidone.为了对膜提供亲水作用， 使用重均分子量小于900, 000的聚乙烯吡咯烷酮则必须允许大量聚乙烯吡咯烷酮保留在膜中。 In order to provide a hydrophilic membrane effect, weight average molecular weight of less than 900, 000 must allow a large polyvinylpyrrolidone polyvinylpyrrolidone remain in the film.这导致从膜中溶出的物质量增加。 This results in an increase in the material eluted from the membrane by mass.如果为了减小从膜中溶出的物质量而减少保留在膜中且重均分子量小于900， OOQ的聚乙烯吡咯烷酮，亲水作用将变得不足。 If in order to reduce the mass was eluted from the membrane and reduce the weight retained in the film-average molecular weight less than 900, OOQ polyvinylpyrrolidone, hydrophilic function becomes insufficient.如果未使用重均分子量为900， 000或以上的聚乙烯吡咯烷酮，在膜的厚部区域亲水性变得不足，由此通过膜内表面的血浆蛋白附着在该厚部区域。 If no weight average molecular weight of 900, 000 or more of polyvinylpyrrolidone, a hydrophilic region in the thick portion of the film becomes insufficient, whereby the film by plasma protein adhered on the surface of the thick portion in the region.总之，不能获得优良的分离特性。 In short, an excellent separation characteristics can not be obtained.

膜内表面的PVP浓度由X线光电子分光镜检查（XPS)确定。 Concentration of PVP membrane surface is determined by X-ray photoelectron spectroscopy (XPS).特别地，通过在双面带上放置样品，用刀具沿纤维轴向切断该样品，展开 In particular, by placing the samples in the double-sided tape, the sample was cut with a cutter along the fiber axis, expand

该切断的样品，使得膜的内表面为上表面，并用传统方法测量PVP浓度，从而膜的内表面完成XPS测量。 The sample was cut such that the inner surface of the film is on the surface, and measuring the concentration of PVP using conventional methods, so that the inner surface of the membrane to complete the XPS measurement.特别地，这里使用的PVP浓度是 In particular, PVP concentration used here is

由表面氮浓度（氮原子浓度）和表面硫浓度（硫原子浓度）确定的浓 Determined by the surface nitrogen concentration (nitrogen concentration) and the surface sulfur concentration (atomic concentration of sulfur) of concentrated

度，其使用测量设备特有的相关灵敏度系数，由Cls, Ols， Nls和S2p 光谱的面积强度获得。 Degree, using a unique correlation coefficient of the sensitivity measuring apparatus, the strength of the area obtained by the Cls, Ols, Nls, and S2p spectra.当聚砜聚合物具有分子式（3)所示的结构时， 可以使用下面的等式（5)计算PVP浓度。 When polysulfone polymer having the structure shown in the formula (3), the concentration of PVP may be calculated using the following equation (5).

本发明的膜包含水不溶性PVP。 Film of the present invention contains a water-insoluble PVP.如果在膜中的全部PVP都是水溶性的，从膜溶出的物质量不可取地增加。 If all of the PVP in the film are water soluble, film mass increases from undesirably eluted.如果全部PVP都是水不溶性的， 由于膜的内表面（或内表面区域）在血浆过滤期间表现出极弱的膨胀特性，因此不能获得优良的蛋白分离性能。 If all of the PVP is water-insoluble, since the inner surface of the membrane (or the inner surface area) during plasma filtration exhibits very weak expansion characteristics, can not obtain an excellent protein separation performance.由于本发明的膜包括适当量的水不溶性PVP，因此其表现出优良的膜性能。 Since the film of the present invention comprises a suitable amount of water-insoluble PVP, which therefore exhibits excellent film properties.

下面描述了本发明的中空纤维膜的制造方法。 The following describes a method of manufacturing a hollow fiber membrane of the present invention.

通过使用一种制造中空纤维膜的方法可以制造本发明的中空纤维膜，包括以下步骤：从双环形喷嘴排出制膜溶液和内部溶液，使排出的混合物通过气隙，在凝固浴中凝固产生的混合物；该方法进一步的特征在于： Can be produced by using a method for producing a hollow fiber membrane of the hollow fiber membrane of the present invention, comprising the steps of: discharging nozzle membrane-forming solution and an internal solution from a double annular shape, the mixture is discharged through an air gap, coagulated in a coagulation bath to produce mixture; the method further comprising:

a)制膜溶液包含疏水聚合物，疏水聚合物的溶剂，和亲水聚合物， 亲水聚合物对疏水聚合物的比率为27 - 60wt%; a) a solution comprising a hydrophobic film-forming polymer, a solvent for the hydrophobic polymer and hydrophilic polymer, the ratio of hydrophilic polymer to hydrophobic polymer is 27 - 60wt%;

b )内部溶液包括水和至少一种溶剂，并具有40 - "wt %的水含量； c)喷嘴处的制膜溶液具有5D。C或以上的温度；d) 凝固浴具有90 - 100。C的温度；和 b) the internal solution comprises water and at least one solvent, and having 40-- "wt% water content; c) a membrane-forming solution having a nozzle at a temperature above or 5D.C; D) having a coagulation bath 90 - 100.C temperature; and

过气隙，在凝固浴中凝固产生的混合物，从而制造出本发明的中空纤维膜，其中所述制膜溶液基本由疏水聚合物、疏水聚合物的溶剂和亲水聚合物组成，所述内部溶液包括特定浓度的聚合物的优良溶剂的水溶液。 Through the air gap, the resulting mixture was coagulated in a coagulation bath, thereby producing a hollow fiber membrane of the present invention, wherein the solution consists essentially of a hydrophobic film-forming polymer, a solvent and a hydrophilic polymer composed of a hydrophobic polymer, the inner an aqueous solution comprising a good solvent for a particular polymer concentration.

关于聚合物的溶剂，可以使用N-甲基-2-吡咯烷酮，N，N-二甲替甲酰胺，N，N-二甲乙酰胺等。 As for the solvent of the polymer, N- methyl-2-pyrrolidone can be used, N, N- dimethylformamide, N, N- dimethylacetamide and the like.当疏水聚合物是聚砜聚合物时，N-甲基-2-吡咯烷酮（以后可以简称为"画P")是优选的。 When the hydrophobic polymer is a polysulfone polymer is, N- methyl-2-pyrrolidone (hereinafter may be simply referred to as "Videos P") is preferable.腿P是对聚砜聚合物具有最高溶解能力的溶剂。 P is a leg having the highest solubility solvents for polysulfone polymer.例如，在室温下NMP的溶解能力约为另一优良溶剂N，N-二甲乙酰胺的1.5倍。 For example, at about room temperature dissolving ability of NMP another good solvent N, 1.5 times of N- dimethylacetamide.在孔径从膜的外表面向内表面连续减小的梯度结构中，为了在膜的内表面上形成允许血浆蛋白通过其中的大孔径的孔，必须增加从内部溶液中的非溶剂引起的液-液相分离开始到相分离（凝固）完成的时间（粒子成长时间）。 Gradient pore structure from the outer surface to reduce the surface of the continuous film, in order to allow the plasma proteins through the large aperture in which the aperture is formed on the inner surface of the film must be increased to cause liquid from the interior of the non-solvent solution - Liquid phase separation start time (the growth time of particles) (solidified) to complete phase separation.与使用其它溶剂的情况相比，通过使用具有极高溶解能力的丽P,聚砜聚合物允许粒子成长时间增加。 Compared with the case of using other solvents, allowing the use of grain growth time is increased by Lai P, polysulfone polymers with high dissolving ability.由于NMP是聚砜聚合物的最好溶剂，因此制膜溶液中聚砜聚合物的分子链良好地缠绕，从而能够获得高强度的膜。 Since NMP is the best solvent for the polysulfone polymer, the membrane thus prepared solution of polysulfone polymer molecular chains wrapped satisfactorily, it is possible to obtain a film having a high strength.因此，当使用聚砜聚合物作为疏水聚合物时，使用NMP以外的溶剂几乎无法得到本发明的膜。 Thus, when using a hydrophobic polymer as a polysulfone polymer, a solvent other than NMP almost impossible to obtain a film of the present invention.

制膜溶液基本由疏水聚合物、诸如聚乙烯吡咯烷酮的特定亲水聚合物和诸如N-曱基-2-吡咯烷酮的特定溶剂组成。 Particular solvent solution of the film consists essentially of a hydrophobic polymer, such as a specific hydrophilic polymer such as polyvinyl pyrrolidone and N- Yue group consisting of 2-pyrrolidone.如果其它添加剂， 例如水、金属盐等本领域公知的传统添加剂加入到制膜溶液中，就难以获得本发明的膜。 If other additives such as water, salts known in the art and other conventional additives were added to the film-forming solution, it is difficult to obtain a film of the present invention.

本发明中使用的制膜溶液中疏水聚合物浓度没有特別地被限定， Membrane-forming solution used in the present invention, the concentration of hydrophobic polymer is not particularly limited,

只要能够从制膜溶液中制造出膜并且制造的膜具有所述要求的膜性能就可以。 As long as the film properties can be produced from the film-forming solution and a film having the film production will be required.疏水聚合物浓度为10-35wt% ,优选10-30wt%。 Concentration of hydrophobic polymer 10-35wt%, preferably 10-30wt%.为了获得 in order to achieve

高通透性能和高分级（截断）分子量，聚合物浓度优选为10-"wt%。 High energy and high permeability grade (cut) the molecular weight, the polymer concentration is preferably 10- "wt%.

制膜溶液中亲水聚合物的量也是重要的。 The amount of the film was hydrophilic polymer is also important.亲水聚合物对疏水聚合 Hydrophilic polymer to hydrophobic polymer

15物的混合比为27 - 60wt%，优选30-60wt%。 15 was mixed ratio of 27 - 60wt%, preferably 30-60wt%.当对牛血浆进行膜内侧向外过滤时，如果亲水聚合物对疏水聚合物的混合比小于27wt% ,蛋白透过率可能减小。 When the inner membrane of bovine plasma was filtered out, if a hydrophilic polymer blend of hydrophobic polymer is less than 27wt%, protein permeability may be reduced.如果混合比超过60wt% ，制膜溶液的粘性减小， 从而在制膜期间可纺性趋向于变差。 If the mixing ratio exceeds 60wt%, the viscosity of the solution film decreases, so that during the film tends to be poor spinnability.

当从喷嘴排出溶液时，制膜溶液的温度是重要的，其为5(TC或以上，优选60 - 100°C。如果温度小于50。C，在制膜期间可纺性趋向于变差。 When the solution is discharged from a nozzle, the solution temperature of the film is made important, which is 5 (TC or more, preferably 60 -. 100 ° C if the temperature is less than 50.C, during the film tends to be poor spinnability.

内部溶液用于形成中空纤维膜的中空部，并包含水和至少一种疏水聚合物的优良溶剂。 Internal solution for forming a hollow portion of the hollow fiber membrane, and the excellent solvent comprising water and at least one hydrophobic polymer.水含量优选为40 - 55wt%。 The water content is preferably 40 - 55wt%.如果水含量小于40wt%，制膜期间可纺性差。 If the water content is less than 40wt%, and poor spinnability during the film.如果水含量大于55wt%,当对牛血浆进行膜内侧向外过滤时，蛋白透过率可能减小。 If the water content is more than 55wt%, when the inner membrane of the bovine plasma was filtered out, protein permeability may be reduced.

气隙表示喷嘴和凝固浴之间的距离。 It represents the gap distance between the nozzle and the coagulation bath.为了获得本发明的膜，气隙(m)对纺速（m/min)的比率非常重要。 To obtain the film of the present invention, the air gap (m) the ratio of the spinning speed (m / min) is very important.这是因为在这样的情况下能够获得本发明的膜结构，即由于制膜溶液与内部溶液中的非溶剂成分接触而引起从制膜溶液的内表面区域到外表面区域的相分离，从制膜溶液的内表面区域到外表面区域的相分离在制膜溶液进入凝固浴之前完成。 This is because in such a case is possible to obtain a film structure of the present invention, i.e., due to contact the non-solvent component of membrane-forming solution and an internal solution to cause phase separation from the inner surface area of ​​the membrane-forming solution to the outer surface area, from the system the inner surface area of ​​the film with the solution to the outer surface area of ​​the film before the completion of the separation of the solution into a coagulation bath.

气隙对纺速的比率优选为0. 01 - 0. lm/ (m/min)，更优选为0. 01 -0. 05m/ (m/min)。 The ratio of air gap spinning speed preferably is 0. 01 - 0. lm / (m / min), more preferably 0. 01 -0 05m / (m / min)..如果气隙对纺速的比率小于0. 01 m/ (m/min)， 就难以得到具有本发明的结构和性能的膜。 If the ratio of the air-gap spinning speed is less than 0. 01 m / (m / min), it is difficult to obtain a film having the structure and properties of the present invention.如果气隙对纺速的比率大于0. lm/ (m/min)，由于施加给膜的高张力而在气隙中发生相当多的断裂，从而不可取地使制备变难。 If the ratio of the air-gap spinning speed greater than 0. lm / (m / min), since the film is applied to the high tension and considerable breakage occurred in the air gap, so that the prepared undesirably becomes difficult.

这里使用的纺速表示当制造一系列中心纤维膜期间未执行伸展操作时的缠巻速度，其中在制膜期间来自喷嘴的制膜溶液与内部溶液一起通过气隙并且在凝固浴中凝固的膜被缠巻。 The spinning speed used herein means that when the stretching speed Volume winding operation is not performed during the manufacture of a series of central fiber membrane, wherein during the film by an air gap with membrane-forming solution from the nozzle and the internal solution in the coagulation bath and the coagulated membrane Volume was wrapped.通过用圆筒等封闭气隙， 并使具有恒定温度和湿度的空气以特定流速流过气隙，从而可以更稳定地制造中空纤维膜。 By blocking cylinders and other air gap, and having a constant temperature and humidity of air flowing through the air gap at a specific flow rate can be more stably manufacturing a hollow fiber membrane.

关于凝固浴，使用聚合物不溶的液体，例如水；酒精，例如甲醇和乙醇；醚；脂肪族烃，例如n (正）-己烷和n-庚烷；等等。 About the coagulation bath, using a liquid polymer is insoluble, for example, water; alcohols, such as methanol and ethanol; ethers; aliphatic hydrocarbons such as n (n) - n- hexane and heptane; and the like.其中水是优选的。 Wherein water is preferred.通过加入溶剂能够控制凝固速度等，其中聚合物少量溶解在凝固浴中。 By adding a solvent capable of controlling the solidification velocity and the like, wherein the polymer is sparingly soluble in the coagulation bath.

当对牛血浆进行膜内侧向外过滤时，蛋白透过率可能减小。 When the inner membrane of bovine plasma was filtered out, protein permeability may be reduced.如果凝固 If solidification

浴的温度为IO(TC或以上，在制膜期间膜不可取地经常断裂。 Bath temperature for IO (TC or more, the film during the film often breaks unpreferably.

为了获得本发明的膜，凝固后膜的厚度对内径的比率为0.15-0.4，优选为0.2-0.3。 To obtain the film of the present invention, the film thickness after the solidification ratio of an inner diameter of 0.15 to 0.4, preferably 0.2 to 0.3.如果膜的厚度对内径的比率小于0. 15,膜的绝对强度趋向于减小。 If the ratio of the thickness of the film is smaller than the inner diameter of 0.15, the absolute strength of the film tends to decrease.如果比率超过0.4，可能得不到具有本发明的梯度结构的膜，在该梯度结构中孔径从膜的外表面向内表面（或内表面区域）减小。 If the ratio exceeds 0.4, the film may not have a gradient structure of the present invention, the pore size of the membrane from the outer surface toward the inner surface (or inner surface area) is reduced in the gradient structure.这是因为，由于制膜溶液中溶剂的量对内部溶液中非溶剂的量的比率大，因此仅使用内部溶液中非溶剂的量，在浸入凝固浴之前不能完成从制膜溶液的内表面区域到外表面区域的相分离。 This is because, since the amount of solvent in the solution film of a large amount of nonsolvent ratio of the internal solution, the internal solution, so only the amount of nonsolvent is not completed within a surface region of the film from the solution prior to immersion in the coagulation bath phase separation of the outer surface area.

膜的外径为400jani或以下，优选为300 pra或以下。 400jani film is an outer diameter or less, preferably 300 pra or less.假设膜的外径增加则模块（module)中的膜面积（填充量）必定减小，结果单位时间的处理能力不可取地减小。 Suppose the outer diameter of the membrane is increased membrane area (filling amount) of the module (Module1) is necessarily reduced, the results of the processing capacity per unit time is reduced undesirably.另一方面，为了在增加膜的外径时在模块中保持膜面积（填充量），模块容器/腔的尺寸必须增大，因此不可取地增加了费用。 On the other hand, in order to maintain the membrane area (loading) in the module when the outer diameter of the film increases, the size of the module container / chamber must be increased, and therefore undesirably increases the cost.假设本发明的膜用于医疗用途，为了减小病人医疗费用方面的负担，必须避免使用昂贵和大型的模块。 Suppose film of the present invention for medical use, in order to reduce the burden of patient care costs, the use of expensive and must avoid a large module.因此由于上述性价比关系，膜的外径优选为400)am或以下。 Cost for the aforementioned relationship, the outer diameter of the film is preferably 400) am or less.

本发明的膜可以是干燥的。 The film of the present invention may be dry.当膜被干燥时膜可以注入或不注入保湿剂，例如甘油。 When the film is dried film may be injected or not injected humectants, such as glycerol.

由于膜中的一部分PVP可以是水不溶性的，通过对膜应用诸如电子束或Y射线的辐射，膜的溶出量可以减小。 Since the portion of the film PVP may be water-insoluble, such as by electron beam or Y ray radiation, the film can reduce the elution amount of film applications.可以在组装模块之前或之后应用辐射。 Radiation may be applied before or after assembly of the module.

用于本发明中的水不溶性PVP的量表示从膜中PVP的总量减去水溶性PVP的量而获得的PVP的量。 The amount of water used in the present invention represents the amount of insoluble PVP is PVP film from the total amount of water-soluble PVP subtracting the PVP is obtained.通过氮和硫的元素分析可以容易地计算膜中PVP的总量。 By elemental analysis of sulfur and nitrogen in the total amount of PVP films can be easily calculated.

水溶性PVP的量可以由下面的方法确定。 The water-soluble PVP can be determined by the following method.

在疏水聚合物为聚砜聚合物的情况下，膜完全溶解在N-甲基-2- In the case where the hydrophobic polymer is a polysulfone polymer, the film was completely dissolved in N- methyl-2

17吡咯烷酮中，在产生的聚合物溶液中加入水以使疏水聚合物完全沉淀。 17 pyrrolidone, water was added to the polymer solution produced in the hydrophobic polymer to complete precipitation.通过使聚合物溶液静置并通过液相色谱法确定上层液体中PVP的量， 从而可以确定水溶性PVP的量。 By determining the amount of the polymer solution was allowed to stand and the supernatant liquid of PVP by liquid chromatography to determine the amount of soluble PVP.

下面参考附图描述了本发明的血浆净化系统的一个实施例。 Described below with reference to the accompanying drawings plasma purification system according to one embodiment of the present invention embodiment.在图4 In FIG. 4

中，从血液入口（ 1 )供给血液回路（2 )的血液在血泵（3)的压力下供给血浆分离器（4)。 In from the blood inlet (1) supplying the blood circuit (2) blood plasma separator is supplied at a pressure of the blood pump (3) (4).通过向整个系统中导入诸如生理盐水溶液的补给溶液，在将血液导入系统之前对系统工况进行充分调整。 , Sufficient to adjust the system operating conditions by introducing replenishing solution such as a physiological saline solution to the entire system before the blood into the system.通过系统工况的调整可以从系统中除去气泡。 Bubbles can be removed from the system by adjusting the operating conditions of the system.

使致病物质已去除或减少的血浆供给第一混合装置U4)以用于混合血浆成分和补给溶液。 Pathogenic substance has been removed or reduced plasma supplied to the first mixing device U4) for mixing a plasma component and replenishment solution.补给溶液通过补给溶液入口（13)导入， 并由补给溶液泵（12 )通过补给溶液导入管（11 )供给第一混合装置(14)。 Solution by replenishing solution supply inlet (13) introduced by replenishing solution pump (12) by introducing the solution supply pipe (11) supplying a first mixing means (14).关于用于混合血浆成分和补给溶液的第一混合装置（14)， 使用管连接器等。 About the mixing apparatus mixing a first component and a plasma replenishing solution (14), using a tube or the like for connection.补给溶液导入到系统和排出液从系统排出可以连续或间断地执行。 Replenishing solution was introduced into the system and the discharge liquid discharge can be performed continuously or intermittently from the system.关于补给溶液，可以使用新鲜冻结血浆，清蛋白制品， 生理盐水溶液等。 About replenishing solution, may be used fresh frozen plasma, albumin products, physiological saline solution or the like.

供给第一混合装置（14)的血浆成分与补给溶液混合，为了混合由血浆分离器（4)分离的血细胞成分，其使用血浆回收泵（17)供给第二混合装置（15)。 Replenishing solution mixed with the first plasma component mixing means (14) is supplied, for mixing the plasma separated by the separator (4) blood cell components, which (17) a second mixing means (15) supplied using plasma collection pump.关于混合血细胞成分和血浆成分的第二混合装置，可以使用静脉腔（venous chamber)等。 Second mixing means mixing on blood cell component and a plasma component may be used vena cava (venous chamber) and the like.已除去或减少致病物质的血浆和血细胞成分混合在第二混合装置中以恢复原来的血液状态， 其通过血液出口（16)回收。 Has been removed or reduced plasma and blood cell components pathogenic agents are mixed in the second mixing means to restore the original state of the blood, which is recovered through a blood outlet (16).

通过重复上述步骤从血液中除去致病物质可以改善疾病。 By repeating the above steps to remove the causative agent of disease from the blood can be improved.血液入口（l)和血液出口（ 16)可以直接与活体连接，由此可以连续进行长时间的治疗。 A blood inlet (l) and a blood outlet (16) can be connected directly to a living body, whereby the treatment can be continued long.

优选使用加热血浆的装置（18)来加热第二混合装置（15)上游的血浆成分。 Heating means preferably plasma (18) upstream of the plasma component to a second heated mixing means (15).如果血浆成分的温度太低，血浆成分可能不利于与血细胞成分均匀混合，或者血浆成分不能直接从血液出口（16)返回活体。 If the temperature is too low plasma component, may not be conducive to the plasma component of blood cell components were uniformly mixed, or plasma component from a living body can not return to the blood outlet (16).关于加热血浆的装置（18),作为举例，可以是使用加热器和/或温水 On plasma heating means (18), by way of example, a heater may be used and / or heated

直接或间接加热血浆的装置。 It means the direct or indirect heating of plasma.

由于血浆成分分离器（7)分离的致病物质的去除效率可以取决于温度而大幅变化，因此导入血浆成分分离器中的血浆可以使用血浆成分加热或冷却装置（19)来保持在所需温度。 Since the plasma component separator (7) the removal efficiency of the separation of pathogenic agents may be greatly changed depending on the temperature, thus introduced into the plasma component separator plasma in the plasma component may be used for heating or cooling means (19) to maintain the desired temperature .在血浆成分加热或冷却装置由于回路配置而不能布置在血浆成分分离器上游的情况下，可以直接加热或冷却血浆成分分离器。 In the case where the plasma component due to the heating or cooling means circuit configuration can not be disposed upstream of the plasma component separator can be directly heated or cooled plasma component separator.关于加热/冷却装置，可以使用在冷却期间直接或间接地使冷水、冷却器等接触血浆成分分离器的装置， 或者在加热期间直接或间接地使温水、加热器等接触血浆成分分离器的装置。 On heating / cooling device, may be used during the cooling of the device contacting the cold plasma component separator, a cooler and the like, directly or indirectly, or during the heating means contacting the heated plasma component separator, such as a heater, directly or indirectly .温度优选为0-"匸的范围。 Temperature is preferably 0 to "Xi range.

在使血液从血液出口（ 16 )直接返回活体的情况下，必须用检测血液中气泡的装置（20) —直监视血液，出自而气泡不会进入返回的血液中。 In the case of blood from a living body to return the blood outlet (16) must be (20) by detecting bubbles in blood apparatus - direct monitoring of blood, by the bubble does not enter the blood returned.关于检测血液中气泡的装置，可以使用气泡检测器（bubble detector )。 Means for detecting air bubbles on the blood, may be used a bubble detector (bubble detector).

去除致病物质之后为了使导入系统的血液的浓度（血细胞浓度） 等于返回系统的血液的浓度（血细胞浓度），优选地，来自血浆成分分离器的排出液的量等于补给溶液的量。 After removal of pathogenic substances introduced for the concentration of the blood system (blood cell concentration) is equal to the concentration in the blood return system (blood cell concentration), preferably, the amount of liquid discharged from the plasma component separator is equal to the supply amount of the solution.为了使排出液的量等于补给溶液的量，可以控制排出泵（9)和补给溶液泵（12)。 In order to discharge the amount of liquid equal to the replenishment amount of the solution may be controlled discharge pump (9) and a solution supply pump (12).然而，由亍排出液的量和补给溶液的量之间的平衡可以随着整个系统上的压力分布的时间性变化而变化，因此优选地使用计算机控制整个系统的泵等。 However, the balance between the amount of liquid discharged from the right foot and the supply amount of the solution may vary with the temporal change of the pressure distribution on the overall system, it is preferable to use a computer to control the entire system of pumps and the like.为了使导入系统的血液的浓度（血细胞浓度）等于返回系统的血液的浓度（血细胞浓度），可以控制每个泵和每个混合装置，使得从血浆分离器到血浆成分分离器的血浆供给量等于返回第二混合装置的血浆量。 In order to make the concentration of blood into the system (the concentration of blood cells) is equivalent to returning concentration in the blood system (concentration of blood cells), you can control each pump and each mixing means, so that the supply amount of the plasma from the plasma separator to the plasma component separator is equal to the amount of plasma returned to the second mixing device.

血液回路、血浆回路和各种导入管和导出管可以使用诸如氯乙烯管这样的用于血液的管。 The blood circuit, a plasma circuit and a variety of inlet and outlet pipe may be used, such as a vinyl chloride pipe of such tubes for blood.阀、夹等可以与该管结合使用。 Valves, clips and the like can be used with the tube.

本发明中的致病物质取决于疾病的类型而不同。 In the present invention, the causative agent of the disease vary depending on the type.因此，本发明可以非限定地应用于下述疾病。 Accordingly, the present invention can be applied to the following non-limiting disease.在疾病是与年龄有关的黄斑变性的情况 In the case of the disease is age-related macular degeneration

下，必须从血液（血浆）中除去诸如纤维蛋白原（Fbg)和免疫球蛋白(IgM)的致病物质。 Next, such as fibrinogen to be removed (the Fbg) and immunoglobulins (IgM) pathogenic substances from the blood (plasma).类似地，在疾病是多发性骨髓癌的情况下，必须除去作为致病物质的M蛋白。 Similarly, in the case of the disease is multiple myeloma, the M protein must be removed as pathogenic agents.在疾病是原发性巨球蛋白血症的情况下， 必须除去Y-球蛋白UgG)。 In the disease is primary macroglobulinemia case, it must be removed Y- globulin UgG).在疾病是重症肌无力症的情况下，必须除去抗乙酰基受体抗体。 In the disease is myasthenia gravis, the acetyl group is necessary to remove the anti-receptor antibody.在疾病是恶性类风湿性关节炎的情况下，必须除去类风湿因子和免疫复合物。 In the case of malignant disease is rheumatoid arthritis, rheumatoid factor must be removed and the immune complexes.在疾病是高脂血症的情况下，必须除去LDL胆固醇。 In the disease is hyperlipidemia cases, you must remove LDL cholesterol.在疾病是重度血液型不相容妊娠的情况下，必须除去Rh血液型不相容致敏性抗体。 In the case where the disease is severe incompatible blood type pregnancy must be removed Rh blood group incompatibility antibody sensitization.在疾病是格-巴二氏综合症的情况下，必须除去脱髓鞘因子和抗体。 In cell disease is - under-Barre syndrome cases, you must remove demyelination factors and antibodies.在疾病是天疱疮的情况下，必须除去抗表皮细胞膜抗体和IgG。 In the case where the disease is pemphigus, it must be removed and antibody against epidermal membrane IgG.在疾病是大疱性类天疱疮的情况下，必须除去抗基底膜抗体和IgG。 In the disease is bullous pemphigoid cases necessary to remove anti-basement membrane antibody and IgG.在疾病是闭塞性动脉硬化的情况下，必须除去LDL胆固醇。 In the case of disease is arteriosclerosis obliterans, you must remove LDL cholesterol.在疾病是肾小球灶性硬化症的情况下，必须除去LDL胆固醇、IgG和C3。 In the disease is focal glomerular sclerosis case, you must remove LDL cholesterol, IgG and C3.在疾病是同种肾移植的情况下，必须除去抗ABO抗体和'淋巴细月包抗体。 In the case where the disease is renal allograft must be removed and the antibodies anti-ABO 'month package lymphocyte antibody.本发明也可以用于病毒性疾病。 The present invention may also be used for viral diseases.

在该情况下，本发明致病物质是病毒。 In this case, the present invention is a viral causative agent.例如，可以是诸如B型肝炎、HIV和病毒性白血球过多症的疾病。 For example, such as Hepatitis B, HIV and viral diseases of the leukocytosis.然而，本发明并不限于这些病毒性疾病。 However, the present invention is not limited to these viral diseases.

实现本发明的最佳方式 Best Mode of the present invention

以下的实施例描述了本发明。 The following examples describe the present invention.然而，本发明并不限于以下实施例。 However, the present invention is not limited to the following embodiments.测量方法如下所述。 The measuring method is as follows.

用作测量样品的中心纤维膜在干燥状态下使用。 Used as a measurement sample used a central fiber membrane in a dry state.(透水量的测量）使纯水（25°C)从有效长度为180mm的纤维束（膜的数量经调整以使内表面面积为110士10cii^的小型模块）的内表面渗透到外表面， 该纤维束的两端都用粘合剂固定，透过的纯水量以单位mL/ (m2，hr，Hg )表示。 (Measurement of water permeability) pure water (25 ° C) an effective length of the fiber bundle from 180mm (the number of the film is adjusted to the inner surface area of ​​110 persons of small modular 10cii ^) penetrate the inner surface to the outer surface, ends of the fiber bundle are secured by adhesive, pure water permeable expressed in units of mL / (m2, hr, Hg).

有效膜面积换算为内表面面积。 An effective membrane area in terms of the surface area.(断裂强度的测量） 使用Shimadzu公司制造的AGS-5D型自动绘图仪，在样品长度为20mm和拉伸速度为300ram/min的情况下测量膜强度。 (Measurement of breaking strength) using Autograph AGS-5D type instrument manufactured by Shimadzu Corporation, a sample length of 20mm and a tensile speed to measure the film strength 300ram / min in the case.(牛血浆评价） (Bovine plasma evaluation)

牛血浆（37°C )以0. 5raL/min供给有效长度为180mm、两端都使用粘合剂固定的纤维束（小型模块）的中心部（内表面侧）的一端，并以0. lmL/min从中空部的另一端排出。 Bovine plasma (37 ° C) at 0. 5raL / min feed an effective length of 180mm, both ends of the fiber bundle is fixed using an adhesive (small block) of the central portion (inner surface side) of the end, and in 0. lmL / min from the other end portion of the discharge space.执4亍该单程操作的交叉流过滤180min。 4 execution of the right foot pass cross-flow filtration operation 180min.通过调整膜的数量而调整纤维束的膜面积，使得以0. 5mL/min 供给的牛血浆量对应的线速度为lcm/min。 Adjusted by adjusting the number of fiber bundles membrane area of ​​the membrane, so that the linear velocity in an amount of bovine plasma 0. 5mL / min was supplied corresponding to lcm / min.均匀地搅拌由180min的过滤获得的全部滤液。 Uniformly stirring the whole filtrate obtained by filtration of 180min.通过确定溶液中和过滤前血浆中每种蛋白的浓度而评价膜性能。 Membrane performance was evaluated by determining the concentration in the solution before filtration and in plasma for each protein.透过率的值由下述等式（6)表示。 Transmittance value represented by the following equation (6).

混合5mL的总蛋白颜色试剂（由Wako Pure化学工业公司制造） 和0. 1mL的溶液（血浆（原溶液）或来自膜的滤液）并使该混合物静置30min之后，使用分光光度计在54G腿的波长测量血浆（原溶液） 中或来自膜的滤液中的蛋白总量（浓度）。 5mL total protein mixed color reagent (manufactured by Wako Pure Chemical Industries, Ltd.) and 0. 1mL solution (plasma (original solution) or filtrate from the membrane) and the mixture was allowed to stand, after 30min, a spectrophotometer in the leg 54G the total amount of protein measured plasma wavelength (original solution) or filtrate from the membrane (concentration).(免疫球蛋白（IgM)浓度的测量） (Immunoglobulins (IgM) measurement of the concentration)

21- 1700")和6. Owt。/。聚乙烯吡咯烷酮（由德国的BASF制造的"K90"， 重均分子量为1,200， 000 )溶解在74.0wtQ/o的N-甲基-2-吡咯烷酮中以获得均匀溶液。制膜溶液中聚乙烯吡咯烷酮对聚砜的混合比为30. Owt % 。制膜溶液保持在60°C ,并与由46wt %的N-甲基-2-吡咯烷酮和54wt %的水的混合溶液组成的内部溶液一起从纺口（双环形喷嘴，0. 1醒-0. 2fflin-0. 3rara，喷嘴温度为60°C，喷嘴处的制膜溶液的温度为60°C )排出。使排出的混合物通过长度为0. 96m的气隙并浸入包含于95士rC的水的凝固浴中。 21-1700 ") and 6. Owt./. Polyvinylpyrrolidone (manufactured by BASF of Germany," K90 ", weight average molecular weight of 1,200, 000) was dissolved in 74.0wtQ / o of N- methyl-2-pyrrolidone to obtain a homogeneous solution. film polyvinylpyrrolidone solution mixing ratio of polysulfone to 30. Owt%. membrane-forming solution is maintained at 60 ° C, with 46wt% of the N- methyl-2-pyrrolidone and 54wt% internal solution was mixed solution of water from the nozzle with the composition of the spinneret (dual annular, 0.1 wake -0. 2fflin-0. 3rara, a nozzle temperature of 60 ° C, the temperature of the film of the solution at the nozzle is 60 ° C ) is discharged. the mixture was discharged through an air gap length of 0. 96m and immersed in water 95 contained in a coagulation bath rC persons.

使用圆柱形管密封从纺口到凝固浴的部分，使得外部空气不能进入其中。 The tube was sealed using a cylindrical opening to a coagulation bath from a spinning portion, so that the outside air can not enter therein.纺速固定在80m/min。 Spinning speed fixed at 80m / min.气隙对纺速的比率为0. 012 m/( m/min )。 Ratio of air gap spinning speed was 0. 012 m / (m / min).切断缠巻的纤维束并用80。 Volume cutting winding with a fiber bundle and 80.C的热水在束的切断面上清洗2小时以从膜上除去残留溶剂。 C hot water for 2 hours to wash the membrane to remove residual solvent from the cut surface of the bundle.使用87。 Use 87.C的热风使膜干燥7小时以获得含水量小于1%的干燥膜。 C, hot air dried film 7 hours to a moisture content of less than 1% of the film obtained was dried.通过对干燥膜应用2. 5Mrad的Y射线使膜的一部分PVP不溶解化。 By application of the dry film 2. 5Mrad Y-ray film so that a portion of the PVP insolubilization.

(膜结构和膜性能的评价） (Evaluation of film properties and film structure)

使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.图1- 3展示出了该实施例中得到的膜的电子显微照片。 FIG 1-3 show electron micrograph of the film obtained in the embodiment.表1展示出了膜结构和膜性能等。 Table 1 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜表现出50kgf/cn^或以上的高断裂强度，并具有50%或以上的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film exhibits 50kgf / or high tensile strength above cn ^, and having a total protein permeability of 50% or more.在牛血浆的膜内侧向外过滤期间，该膜长时间保持稳定的过滤量而不发生快速堵塞。 During the filtration membrane outwardly of the inner bovine plasma, the film is stable over time without undergoing rapid filtration amount of clogging.

〈实施例2〉 <Example 2>

除了使用由54wt %的N-曱基-2-吡咯烷酮和46wt %的水的混合溶液组成的内部溶液之外执行与实施例1相同的操作（含水量为46 wt %)。 Except that the internal solution of 54wt% of 2-pyrrolidone and N- Yue group 46wt% of a mixed solution composed of water addition to performing the same operation as in Example 1 (moisture content of 46 wt%).使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表1展示出了膜结构和膜性能。 Table 1 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜表现出50kgf/cr^或以上的高断裂强度，并具有50%或以上的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film exhibits 50kgf / cr ^ or more high breaking strength, and having a total protein permeability of 50% or more.在牛血浆的膜内侧向外过滤期间，该膜长时间保持稳定的过滤量而不发生快速堵塞。 During the filtration membrane outwardly of the inner bovine plasma, the film is stable over time without undergoing rapid filtration amount of clogging.

22〈实施例3〉 22 <Example 3>

除了使用由58wt %的N-甲基-2-吡咯烷酮和42wt %的水的混合溶液组成的内部溶液之外执行与实施例1相同的操作（含水量为42wt % )。 Except that the internal solution of 58wt% of N- methyl-2-pyrrolidone and water, a mixed solution of 42wt% of the composition other than to perform the same operation as in Example 1 (moisture content of 42wt%).使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表l展示出了膜结构和膜性能。 Table l show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜表现出50kgf7cii^或以上的高断裂强度，并具有50%或以上的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film exhibits high tensile strength 50kgf7cii ^ or more, and having a total protein permeability of 50% or more.在牛血浆的膜内侧向外过滤期间，该膜长时间保持稳定的过滤量而不发生快速堵塞。 During the filtration membrane outwardly of the inner bovine plasma, the film is stable over time without undergoing rapid filtration amount of clogging.〈实施例4〉 <Example 4>

除了将制膜溶液中聚乙烯吡咯烷酮和N -甲基-2 -吡咯烷酮的量分别变为10. Owt。 Except that the film solution of polyvinylpyrrolidone and N - methyl - 2 - pyrrolidone amounts were changed to 10. Owt./。 /.和70wt。 And 70wt./。 /.之外执行与实施例l相同的操作。 Addition to performing the same procedure as described in Example l.制膜溶液中聚乙烯吡咯烷酮对聚砜的比率为50. Owt%。 Film solution ratio of polyvinyl pyrrolidone to the polysulfone 50. Owt%.使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表1展示出了膜结构和膜性能。 Table 1 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时， 该膜表现出50kgf/cW或以上的高断裂强度，并具有50%或以上的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film exhibits high tensile strength 50kgf / cW or more, and having a total protein permeability of 50% or more.在牛血浆的膜内侧向外过滤期间，该膜长时间保持稳定的过滤量而不发生快速堵塞。 During the filtration membrane outwardly of the inner bovine plasma, the film is stable over time without undergoing rapid filtration amount of clogging.〈实施例5〉 <Example 5>

除了使用具有8, Owto/。 In addition to having 8, Owto /.的聚乙烯吡咯烷酮和70wt。 Polyvinylpyrrolidone and 70wt./。 /.的N-曱基-2-吡咯烷酮的制膜溶液之外执行与实施例l相同的操作。 It performs the same operation in Example l N- outside the membrane-forming solution Yue-2-pyrrolidone.制膜溶液中聚乙烯吡咯烷酮对聚砜的比率为40. Owt% 。 Film solution ratio of polyvinyl pyrrolidone to the polysulfone 40. Owt%.使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表1展示出了膜结构和膜性能。 Table 1 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜表现出50kgf/cn^或以上的高断裂强度，并具有50%或以上的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film exhibits 50kgf / or high tensile strength above cn ^, and having a total protein permeability of 50% or more.在牛血浆的膜内侧向外过滤期间，该膜长时间保持稳定的过滤量而不发生快速堵塞。 During the filtration membrane outwardly of the inner bovine plasma, the film is stable over time without undergoing rapid filtration amount of clogging.〈对比实施例1〉 <Comparative Example 1>

除了使用由43wt %的N-甲基-2-吡咯烷酮和57wt %的水的混合溶液组成的内部溶液之外执行与实施例1相同的操作（含水量为57wt%)。 Except that the internal solution of 43wt% of N- methyl-2-pyrrolidone and water, a mixed solution of 57wt% of the composition other than to perform the same operation as in Example 1 (moisture content of 57wt%).使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表2展示出了膜结构和膜性能。 Table 2 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜具有小于50。 When the inner membrane of bovine plasma was filtered out, the film is less than 50./。 /.的总蛋白透过率。 The total protein transmittance.〈对比实施例2〉 <Comparative Example 2>

除了使用由62wt %的N-甲基-2-吡咯烷酮和38wt %的水的混合溶液组成的内部溶液之外执行与实施例1相同的操作（含水量为38wt o/o )。 Except that the internal solution of 62wt% of N- methyl-2-pyrrolidone and water, a mixed solution of 38wt% of the composition other than to perform the same operation as in Example 1 (moisture content of 38wt o / o).然而，由于频繁断裂而不能进行纺膜。 However, due to frequent film rupture can not be spun.〈对比实施例3〉 <Comparative Example 3>

除了将制膜溶液中聚乙烯吡咯烷酮和N-甲基-2-吡咯烷酮的量分别变为5. Owt。 The film except that the amount of polyvinylpyrrolidone solution and N- methyl-2-pyrrolidone were changed 5. Owt./。 /.和75. Owt。 And 75. Owt./。 /.之外执行与实施例1相同的操作。 It performs the same operation as in Example 1 outside.制膜溶液中聚乙烯吡咯烷酮对聚砜的比率为25.0wt%。 Film polyvinylpyrrolidone solution ratio of polysulfone was 25.0wt%.使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表2展示出了膜结构和膜性能。 Table 2 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜具有小于50%的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film has a total transmittance of less than 50% of the protein.〈对比实施例4〉 <Comparative Example 4>

混合实施例1中使用的20wt。 20wt mixture used in Example 1 embodiment./。 /.的聚砜、13wt。 Polysulfone, 13wt./o的聚乙烯吡咯烷酮和67wt%的N-曱基-2-吡咯烷酮。 / O polyvinylpyrrolidone and 67wt% of N- Yue-2-pyrrolidinone.然而，不能获得均匀的溶液。 However, a homogeneous solution can not be obtained.〈对比实施例5〉 <Comparative Example 5>

除了将制膜溶液和喷嘴温度变为45。 Except that the membrane-forming solution and a nozzle temperature was changed to 45.C之外执行与实施例2相同的操作（喷嘴处的制膜溶液的温度为45°C )。 Performs the same operation as in Example 2 other than C (temperature of the membrane of the solution at the nozzle is 45 ° C).然而，由于频繁断裂而不能进行纺膜。 However, due to frequent film rupture can not be spun.〈对比实施例6> <Comparative Example 6>

除了将溶剂从N-曱基-2-吡咯烷酮变为N, N-二甲乙酰胺之外执行与实施例l相同的操作。 Apart from the solvent-yl-2-pyrrolidone N- Yue becomes N, the embodiment performs the same operation than in Example l N- dimethylacetamide.使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表2展示出了膜结构和膜性能。 Table 2 show the membrane structure and membrane performance.当对牛血浆进行膜内侧向外过滤时，该膜具有小于50% 的总蛋白透过率。 When the inner membrane of bovine plasma was filtered out, the film has a total transmittance of less than 50% of the protein.〈对比实施例7〉 <Comparative Example 7>

除了使用95wt %的N， N-二甲乙酰胺和5wt %的水的混合溶液作为内部溶液之外执行与对比实施例6相同的操作。 Except that 95wt% of N, N- dimethylacetamide and 5wt% of a mixed solution of water was used as the internal solution performs the same operation as in Comparative Example 6.使用电子显微镜观察得到的膜，发现膜具有孔径从膜的外表面向内表面连续减小的海绵结构。 Obtained film was observed using an electron microscope, it was found sponge structure having a pore size of the membrane from the outer surface of the film surface continuously decreasing.表2展示出了膜结构和膜性能。 Table 2 show the membrane structure and membrane performance.由于对牛血浆进行膜内侧向外过滤之后35min时产生的压力（堵塞）快速增加，因此评价中断。 Since bovine plasma was generated when the pressure side of the membrane filter after 35min outwardly (clogging) rapidly, thus interrupting the evaluation.〈对比实施例8〉 <Comparative Example 8>

除了使用由日本专利申请特开昭58-155865的实施例1中公开的方法获得的、内径200)am、厚度46 ji m的中空纤维膜之外，以与实施例1中公开的相同方式进行牛血浆评价。 In addition to using the method of Japanese Patent Application Laid-Open No. Sho 58-155865 as in Example 1 to obtain the disclosure, the inner diameter 200) am, the thickness of the hollow fiber membranes 46 ji m outside, in the same manner as in Example 1 were disclosed in evaluation of bovine plasma.由于对牛血浆进行膜内侧向外过滤之后120min时产生的压力（堵塞）快速增加，因此评价中断。 Since the inner membrane of the bovine plasma was then filtered outward pressure generated at 120min (clogging) rapidly, thus interrupting the evaluation.

实施例1的11,400膜形成束并在两端固定到圓柱形外壳，该外壳使用聚氨酯树脂形成有效膜面积为2m2的模块。 Example 1 11,400 embodiment film formed into a beam and at both ends secured to the cylindrical housing, the housing is formed using a polyurethane resin 2m2 effective membrane area of ​​a module.所述模块用作为血浆成分分离器。 The module is used as the plasma component separator.使用作为血浆分离器的Plasmaflow (由Asahhi医疗公司制造，膜面积为0. 8m2)形成与图4中所示的系统类似的系统，使用该系统处理人体血液3小时。 Plasmaflow used as the plasma separator (Asahhi manufactured by Medical membrane area of ​​0. 8m2) are formed in the system shown in FIG. 4 a similar system, using the blood processing system for 3 hours.

作为目标血液使用与年龄有关的黄斑变性患者的血液，系统直接连接人体。 Use in patients with age-related degeneration of the macula as the target blood in the blood, the system directly connected to the human body.

在10天的时间内进行4次上述治疗。 Four times the above-described treatment within 10 days.结果，第二次治疗后停止随时间变化的视觉灵敏度降低，第四次治疗后视力得到改善。 As a result, treatment is stopped after the second time varying visual acuity decreased visual acuity improved after the fourth treatment.治疗前血液中纤维蛋白原和免疫球蛋白的值分别是320mg/dL和120mg/dL。 Pretreatment fibrinogen level in the blood and immunoglobulins were 320mg / dL and 120mg / dL.治疗后这些值明显地分别减小到140mg/dL和40 mg/dL。 After treatment, these values ​​were significantly reduced to 140mg / dL and 40 mg / dL.〈实施例7〉 <Example 7>

根据本发明，获得一种优良的血浆净化膜和一种优良的血液净化系统，该膜很少堵塞，并在使用膜内侧向外过滤的血浆净化期间具有高强度。 According to the present invention, to obtain a good and an excellent plasma purification membrane blood purification system, the film is rarely clogged, and high strength during use of the plasma side of the membrane filtration purification outwardly.因此，本发明能够用于药物用途、医疗用途和一般工业用途。 Accordingly, the present invention can be used for pharmaceutical use, medical uses and general industrial uses.

Claims (25)

Translated from Chinese

1. 一种中空纤维血浆净化膜，包含疏水聚合物和亲水聚合物并具有海绵结构，在该结构中孔径从膜的外表面向内表面连续减小，具有50kgf/cm2或以上的断裂强度，当对牛血浆进行膜内侧向外过滤时，总的蛋白透过率为50％或以上，免疫球蛋白IgM透过率为90％或以下。 1. A hollow fiber plasma purification membrane, comprising a hydrophobic polymer and a hydrophilic polymer and having a sponge structure, the pore size successively decreases from the inner surface of the outer surface of the film structure, or having a breaking strength of at least 50kgf / cm2, when the inner membrane of bovine plasma was filtered out, the total protein permeability of 50% or more, the transmittance of IgM of 90% or less.

2. 根据权利要求1所述的中空纤维血浆净化膜，所述膜的外表面上具有圆形或椭圆形孔，所述孔具有1 4m或以上的平均孔径。 2. The hollow fiber according to claim 1 plasma purification membrane, the outer surface of the membrane has a circular or oval apertures having an average pore diameter of 1 or more 4M.

3. 根据权利要求1或2所述的中空纤维血浆净化膜，其中膜的外表面的孔隙率为10%或以上。 3. The hollow fiber plasma purification membrane according to claim 1 or claim 2, wherein the porosity of the outer surface of the film is 10% or more.

7. 根据权利要求6所述的中空纤维血浆净化膜，其中聚乙烯吡咯烷酮具有900， 000或以上的重均分子量。 7. The hollow fiber of claim plasma purification membrane according to claim 6, wherein the polyvinylpyrrolidone has a 900, 000 or more weight average molecular weight.

9. 根据权利要求1或2所述的中空纤维血浆净化膜，其中所迷膜用于治疗与年龄有关的黄斑变性患者。 9. The hollow fiber plasma purification membrane according to claim 1 or claim 2, wherein the fans of age-related degeneration patients for the treatment of macular membrane.

10. 根据权利要求6所述的中空纤维血浆净化膜，其中所述膜用于治疗与年龄有关的黄斑变性患者。 10. The hollow fiber according to claim 6, said plasma purification membrane, wherein the membrane for the treatment of patients with age-related degeneration of the macula.

11. 根据权利要求7所述的中空纤维血浆净化膜，其中所述膜用于治疗与年龄有关的黄斑变性患者。 The hollow fiber according to claim 7, wherein said plasma purification membrane, wherein the membrane for the treatment of patients with age-related degeneration of the macula.

12. 根据权利要求1或2所述的中空纤维血浆净化膜，其中所述膜用于治疗高脂血症患者。 12. The hollow fiber plasma purification membrane according to claim 1 or claim 2, wherein said film is used for the treatment of patients with hyperlipidemia.

13. 根据权利要求6所述的中空纤维血浆净化膜，其中所述膜用于治疗高脂血症患者。 13. The hollow fiber according to claim 6, said plasma purification membrane, wherein the membrane for treating patients with hyperlipidemia.

14. 根据权利要求7所述的中空纤维血浆净化膜，其中所述膜用于治疗高脂血症患者。 14. The hollow fiber according to claim 7, said plasma purification membrane, wherein the membrane for treating patients with hyperlipidemia.

15. —种制造中空纤维血浆净化膜的方法，该膜包含疏水聚合物和亲水聚合物并具有海绵结构，在该结构中孔径从膜的外表面向内表面连续减小，具有50kgf/cn^或以上的断裂强度，当对牛血浆进行膜内侧向外过滤时，总的蛋白透过率为50%或以上，免疫球蛋白IgM透过率为90%或以下，该方法包括以下步骤：从双环形喷嘴排出制膜溶液和内部溶液，使排出的混合物通过气隙，在凝固浴中凝固；该方法进一步的特征在于：a) 制膜溶液包含疏水聚合物，疏水聚合物的溶剂，和亲水聚合物， 亲水聚合物对疏水聚合物的比率为27 - 60wt%;b) 内部溶液包含水和至少一种溶剂，并具有40 - 55wt。 15. The - method for producing a hollow fiber plasma purification membrane, the membrane comprising a hydrophobic polymer and a hydrophilic polymer and having a sponge structure, the pore size successively decreases from the inner surface of the outer surface of the film structure having 50kgf / cn ^ breaking strength or more, when the inner membrane of the bovine plasma was filtered out, the total protein permeability of 50% or more, the transmittance of IgM of 90% or less, the method comprising the steps of: from double annular nozzle discharging the film solution and the internal solution, the mixture is discharged through an air gap, the coagulation in the coagulation bath; the method further characterized by: a) a solution comprising a hydrophobic film-forming polymer, a solvent for the hydrophobic polymer, and pro hydrophilic polymers, and the ratio of hydrophilic polymer to hydrophobic polymer is 27 - 60wt%; b) the internal solution comprises water and at least one solvent, and having a 40 - 55wt./。 /.的水含c) 喷嘴处的制膜溶液具有50。 Containing water c) a solution of film 50 having a nozzle.C或以上的温度；d) 凝固浴具有90 - 100。 C or a temperature above; D) having a coagulation bath 90--100.C的温度；和e) 气隙对纺速的比率为0. 01 - 0. 1m/ (m/min)。 C temperature; and e) an air gap ratio of the spinning speed is 0. 01 - 0. 1m / (m / min).

16. 根据权利要求15所述的制造中空纤维血浆净化膜的方法，进一步包括对膜应用辐射的步骤。 16. A method of plasma purification membrane according to claim 15 for manufacturing a hollow fiber according to claim, further comprising the step of film applications of radiation.

17. 根据权利要求15所述的制造中空纤维血浆净化膜的方法，其中疏水聚合物是聚砜聚合物。 17. A method of plasma purification membrane according to claim 15 for manufacturing a hollow fiber according to claim, wherein the hydrophobic polymer is a polysulfone polymer.

18. 根据权利要求15或17所述制造中空纤维血浆净化膜的方法， 其中疏水聚合物的溶剂是N-甲基-2-吡咯烷酮。 18. The method of 15 or 17 for producing a hollow fiber plasma purification membrane according to claim, wherein the hydrophobic polymer solvent is N- methyl-2-pyrrolidone.

19. 根据权利要求15或17所述制造中空纤维血浆净化膜的方法，其中纺速为60m/min或以上。 19. The method of 15 or 17 for producing a hollow fiber plasma purification membrane according to claim, wherein the spinning speed was 60m / min or more.

20. —种血浆净化系统，其包括：血浆分离器，其包括将血液分离成血细胞成分和血浆成分的分离膜；血浆成分分离器，其包括将分离的血浆成分分离成致病物质和致病物质已除去或减少的血浆成分的分离膜；第一混合装置，其用于混合致病物质已除去或减少的血浆成分和补给溶液；第二混合装置，其用于进一步混合经过第一混合装置的血浆成分和血浆分离器分离的血细胞成分；其中包括在血浆成分分离器中的分离膜是根据权利要求1 - 14中任一所述的膜。 20. - species plasma purification system, comprising: a plasma separator, comprising separating blood into a blood cell component and a plasma component separation; plasma component separator, which comprises separating the separated plasma component into pathogenic substances and pathogenic plasma component separation material has been removed or reduced; a first mixing means for mixing the causative agent has been removed or reduced plasma component and replenishing solution; second mixing means for further mixing through the first mixing means the plasma component separated by the separator and the plasma component of blood cells; - a membrane according to any separation membrane 14 which comprises a plasma component separator according to claim 1.

21. 根据权利要求20所述的血浆净化系统，进一步包括加热混合血浆成分和血细胞成分的第二混合装置上游的血浆的装置。 21. The plasma purification system according to claim 20, further comprising a second mixing means of plasma heating means upstream of the mixing of blood plasma component and the cell components.

23. 根据权利要求20-22任一项所述的血浆净化系统，其中从血浆成分分离器排出的包含致病物质的排出液量等于补给溶液的量。 23. The plasma purification system according to any of claims 20-22, comprising a liquid discharge amount of the pathogenic substances discharged from the plasma component separator is equal to the amount of replenishing solution.

24. 根据权利要求20-22任一项所迷的血浆净化系统，其这样控制，使得从血浆分离器到血浆成分分离器的血浆供给量等于返回到笫二混合装置的血浆量。 24. The plasma purification system according to any one of the 20-22 fans claim controlled so that plasma from the plasma separator to the supply amount of the plasma component separator is equal to the amount of plasma returned to the undertaking of two mixing apparatus.

25. 根据权利要求24所述的血浆净化系统，进一步包括检测第二混合装置下游和血液出口上游的血液中的气泡的装置。 25. The plasma purification system according to claim 24, further comprising detecting a blood outlet and a second mixing means upstream of the downstream apparatus of bubbles in the blood.